Leveraging Reactivation of Tissue-Resident Memory T Cells in the Tumor Microenvironment for Oncolytic Virotherapy
Abstract
Scientific Objective and Rationale A brain cancer is a disease that occurs in brain where malignant cells grow fast and form a mass of abnormal tissue. Brain cancers are the leading cause of cancer death in United States (U.S.) active-duty military. Glioblastoma multiforme (GBM) is the most common and aggressive brain cancer in adults. GBM is a rare cancer with an incidence of 3.21 per 100,000 persons in the U.S. It causes around 12,000 new cases, but 10,000 deaths each year. GBM remains invariably lethal. Nearly all GBM patients die within 2 years of diagnosis. There is no effective treatment for GBM so far. Immunotherapy is a type of cancer treatment that helps to boost the immune system and enables it to effectively fight cancer cells. Immunotherapy is bringing great promise to several types of cancers and is being actively pursued for GBM treatment. However, so far it has not benefitted GBM patients, largely due to (1) lack of enough immune cells within the tumor itself that can kill the GBM cells and (2) inactivation of immune cells mediated by the GBM cells. Significant efforts are now underway to develop the means of increasing and activating immune cells in the GBM tumors. The human body encounters many different viral infections throughout its life, such as flu and COVID-19. Tissue-resident memory T (T<RM>) cells are a group of special immune cells that can be developed and remain long-term after an infection has been eliminated by immune response in the body. Those memory T cells permanently reside in different tissues, including tumors, throughout the entire body. T<RM> cells can remember a previous infection and quickly become activated to fight a past infection upon reexposure to a previously encountered virus. Importantly, the reactivated T<RM> cells can recruit and activate other immune cells, and make them join the fighting. Recent research found that T<RM> cells not only protect the body against viral infection, but also cancer development. Our previous work showed that T<RM> cells specific to common human viruses, including flu, are present in patient GBM tumors and can be activated by viral peptides that are derived from a previously encountered virus. In mouse model, we found that applying viral peptides to reactivate T<RM> cells within GBM tumors is a highly effective means of immune activation that recruits more immune cells to GBM tumors and suppresses tumor growth. Our current work found that T<RM> cell-activating viral peptides significantly improve the antitumor efficacy of an oncolytic (or tumor killing) herpes simplex virus (oHSV) against GBM. oHSV is a well-studied antitumor agent, engineered in the laboratory to selectively kill cancer cells without harming healthy cells. oHSV infects cancer cells and makes copies of itself until the cell bursts, causing cell death and the release of special danger signals that help to generate an immune response against the tumor. One oHSV has been approved in the U.S. for melanoma treatment and the other in Japan for brain cancer. Despite the progress in clinic, the efficacy of oHSV therapy is limited and needs improvement. Given the common roles of T<RM> cells and oHSV in stimulating immune activation in tumor, our hypothesis is that T<RM> cell reactivation improves oHSV efficacy against GBM by promoting the antitumor immune response. Our objective is to develop a new oHSV-T<RM> cell based immunotherapy with translatable, clinical potential for human GBM by testing our hypothesis. We will validate this novel oHSV- T<RM> cell immunotherapy and understand how it works to kill the GBM tumor in our proposed research. Focus Area: The proposed work addresses Therapy, one of the Fiscal Year 2022 Rare Cancers Research Program Focus Areas. The proposed research has the potential to innovate a therapeutic platform that meaningfully impacts the survival and quality of life for GBM patients, including those who are active-duty S
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310448
Entities
People
- Jianfang Ning
Organizations
- United States Army
- University of Minnesota